Brain injury as a result of head trauma is a major health problem in the United States. Presently, little is known about the complex response of the CNS following cortical and injury and what possible therapeutic regimes can be employed to assist in recovery. When injured, growth- quiescent neurons in the CNS initiate a reactive repair process which appears to underlie functional recovery. This process can only be successful if the basic substrate, viable neurons and processes, are available. A common outcome of head trauma is secondary neuronal injury which appears to progress temporally and renders potentially reactive tissue unresponsive. Cytokines, secreted by injury-activated brain cells, initiate the production of numerous trophic factors that may protect neuron and their processes from secondary injury, thus promoting brain self-repair. Proposed experiments will explore the mechanisms involved in the injured cortex to compensate following focal trauma. These studies use a reliable animal model of brain injury in F344 rats caused by controlled cortical deformation. Study 1 examines the hypothesis that following cortical contusion, the injured brain activates a self-repair process and replaces lost synaptic connections. These experiments involve quantitative light and ultrastructural techniques. Study 2 examines the hypothesis that following injury there is a temporal sequence in the production of specific CNS protein which play a role in the compensatory process. These experiments involve quantitative immunocytochemistry and biochemical techniques to assess regional distribution after injury. Study 3 examines the hypothesis that cytokines and trophic agents influence neuronal plasticity and survival by affecting cellular calcium (Ca2+) homeostasis. These in vitro experiments will study the effects of IL-1 & 6 and NGF,bFGF,IGF-1 and IGF-II on neurite outgrowth and cell survival coupled with pharmacological manipulations of Ca2+. Possible modulatory effects of these agents on hypoglycemic and anoxic neuronal damage will be examined. Study 4 examines the hypothesis that intraventricular infusion of cytokines and trophic factors can enhance the self-repair process by altering cell survival and synapse replacement. Experiments involved the micro-infusion of trophic factors such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF), insulin-like growth factor-I&II (IGF-1; IGF-II) and ultrastructural evaluation of the neuropil.